RESUMO
Prolyl hydroxylase domain-containing protein (PHD) inhibitors are useful as orally administered agents for the treatment of renal anemia. Based on the common structures of known PHD inhibitors, we found novel PHD inhibitor 1 with a 2-[(4-hydroxy-6-oxo-2,3-dihydro-1H-pyridine-5-carbonyl)amino]acetic acid motif. The PHD2-inhibitory activity, lipophilicity (CLogP), and PK profiles (hepatocyte metabolism, protein binding, and/or elimination half-life) of this inhibitor were used as the evaluation index to optimize the structure and eventually discovered clinical candidate 42 as the suitable compound. Compound 42 was demonstrated to promote the production of erythropoietin (EPO) following oral administration in mice and rats. The predicted half-life of this compound in humans was 1.3-5.6â¯h, therefore, this drug may be expected to administer once daily with few adverse effects caused by excessive EPO production.
Assuntos
Ácido Acético/farmacologia , Anemia/tratamento farmacológico , Descoberta de Drogas , Prolina Dioxigenases do Fator Induzível por Hipóxia/antagonistas & inibidores , Inibidores de Prolil-Hidrolase/farmacologia , Insuficiência Renal Crônica/tratamento farmacológico , Ácido Acético/administração & dosagem , Ácido Acético/química , Administração Oral , Anemia/metabolismo , Animais , Cães , Relação Dose-Resposta a Droga , Humanos , Prolina Dioxigenases do Fator Induzível por Hipóxia/metabolismo , Camundongos , Estrutura Molecular , Inibidores de Prolil-Hidrolase/administração & dosagem , Inibidores de Prolil-Hidrolase/química , Ratos , Insuficiência Renal Crônica/metabolismo , Relação Estrutura-AtividadeRESUMO
Novel (4-piperidinyl)-piperazine derivatives were synthesized and evaluated as ACC1/2 non-selective inhibitors. Optimization of the substituents on the nitrogen of the piperidine ring led to the identification of the fluorine substituted tert-butoxycarbonyl group. Advanced analog, 1,1,1-trifluoro-2-methylpropan-2-yl 4-{4-[(2-amino-6-methyl-1-benzothiophen-3-yl)carbonyl]piperazin-1-yl}piperidine-1-carboxylate (12c) showed potent inhibitory activities in enzyme-assay and cell-based assays. Compound 12c also exhibited reduction of hepatic de novo fatty acid synthesis in rats after oral administration.
Assuntos
Acetil-CoA Carboxilase/antagonistas & inibidores , Flúor/química , Ésteres do Ácido Fórmico/química , Piperazinas/síntese química , Piperidinas/síntese química , Acetil-CoA Carboxilase/classificação , Administração Oral , Animais , Estrutura Molecular , Piperazina , Piperazinas/química , Piperazinas/farmacologia , Piperidinas/química , Piperidinas/farmacologia , Ratos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Acetyl-CoA carboxylases (ACCs), the rate limiting enzymes in de novo lipid synthesis, play important roles in modulating energy metabolism. The inhibition of ACC has demonstrated promising therapeutic potential for treating obesity and type 2 diabetes mellitus in transgenic mice and preclinical animal models. We describe herein the structure-based design and synthesis of a novel series of disubstituted (4-piperidinyl)-piperazine derivatives as ACC inhibitors. Our structure-based approach led to the discovery of the indole derivatives 13i and 13j, which exhibited potent in vitro ACC inhibitory activity.
Assuntos
Acetil-CoA Carboxilase/antagonistas & inibidores , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Piperazinas/farmacologia , Piperidinas/farmacologia , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Modelos Moleculares , Estrutura Molecular , Piperazinas/síntese química , Piperazinas/química , Piperidinas/síntese química , Piperidinas/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Acetyl-CoA carboxylases (ACCs), the rate limiting enzymes in de novo lipid synthesis, play important roles in modulating energy metabolism. The inhibition of ACC has demonstrated promising therapeutic potential for treating obesity and type 2 diabetes mellitus in transgenic mice and preclinical animal models. We describe herein the synthesis and structure-activity relationships of a series of disubstituted (4-piperidinyl)-piperazine derivatives as a new platform for ACC1/2 non-selective inhibitors.
Assuntos
Acetil-CoA Carboxilase/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Piperazinas/farmacologia , Piperidinas/farmacologia , Cristalografia por Raios X , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Modelos Moleculares , Estrutura Molecular , Piperazinas/síntese química , Piperazinas/química , Piperidinas/síntese química , Piperidinas/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Dipeptidyl peptidase IV (DPP-IV) inhibitors have attracted attention as potential drugs for use in the treatment of type 2 diabetes because they prevent the degradation of glucagon-like peptide-1 (GLP-1) and extend its duration of action. We previously reported that 2-cyano-4-fluoropyrrolidines act as potent DPP-IV inhibitors and have been modifying the 1-position of pyrrolidine to obtain more useful inhibitors. An L-tert-butylglycine derivative was found to be a stable and potent DPP-IV inhibitor that exhibits a glucose lowering effect in vivo. Here, we report the synthesis of and biological data on the aforementioned derivatives.
Assuntos
Inibidores da Dipeptidil Peptidase IV/síntese química , Animais , Cristalografia por Raios X , Diabetes Mellitus Tipo 2/enzimologia , Inibidores da Dipeptidil Peptidase IV/química , Inibidores da Dipeptidil Peptidase IV/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Camundongos , Prolina/química , Relação Estrutura-Atividade , Valina/química , Valina/farmacologiaRESUMO
Dipeptidyl peptidase IV (DPP-IV) inhibitors are promising antidiabetic drugs, and several drugs are in the developmental stage. We previously reported that the introduction of fluorine to the 4-position of 2-cyanopyrrolidine enhanced the DPP-IV inhibitory effect. In the present report, we examined the structure-activity relationship (SAR) of 2-cyano-4-fluoropyrrolidine with N-substituted glycine at the 1-position. We report the identification of a potent and stable DPP-IV inhibitor (TS-021) with a long-term persistent plasma drug concentration and a potent antihyperglycemic activity.
Assuntos
Cianetos/química , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Pirrolidinas/síntese química , Pirrolidinas/farmacologia , Animais , Glicemia/metabolismo , Compostos de Flúor/sangue , Compostos de Flúor/síntese química , Compostos de Flúor/química , Compostos de Flúor/farmacologia , Insulina/sangue , Masculino , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteases/sangue , Inibidores de Proteases/química , Pirrolidinas/sangue , Pirrolidinas/química , Ratos , Relação Estrutura-AtividadeRESUMO
Dipeptidyl peptidase IV (DPP-IV) inhibitors have attracted attention as potential drugs for use in the treatment of type 2 diabetes because they prevent degradation of glucagon-like peptide-1 (GLP-1) and extend its duration of action. A series of 2-cyanopyrrolidines are among the most potent of DPP-IV inhibitors. We focused our attention on substitutions at the 3- or 4-position of 2-cyanopyrrolidines and synthesized and evaluated various derivatives. Among them, the 4-fluoro derivative was found to exhibit better DPP-IV inhibitory activity and higher plasma drug concentrations after oral administration to rats than the 4-unsubstituted derivative. We report here on the synthesis and biological data of the aforementioned derivatives.